Crosstalk Between Nitric Oxide and Endocannabinoid Signaling Pathways in Normal and Pathological Placentation

Endocannabinoids are a group of endogenous lipid mediators that act as ligands of cannabinoid and vanilloid receptors, activating multiple signal transduction pathways. Together with enzymes responsible for their synthesis and degradation, these compounds constitute the endocannabinoid system (ECS), which is involved in different physiological processes in reproduction. The placenta, which is essential for the success of gestation and optimal fetal growth, undergoes constant tissue remodeling. ECS members are expressed in trophoblast cells, and current evidence suggests that this system is involved in placental development, apoptosis, and syncytialization. Impairment of endocannabinoid signaling has been associated with several pathological conditions such as intrauterine growth restriction and preeclampsia. Both clinical entities are characterized by dysregulation on vascular perfusion where nitrergic system performs a pivotal role. Nitric oxide (NO) is a potent local vasodepressor that exerts a critical role in the regulation of hemodynamic flow, contributing to the maintenance of low vascular resistance in the feto-placental circulation. NO production could be affected by different factors and growing evidence suggests that the endocannabinoid mediators may regulate nitrergic signaling. Herein, we review emerging knowledge supporting ECS-mediated regulation of NO production in normal placentation. Finally, we discuss how alterations in these systems could affect homoeostasis and contribute to the occurrence of placental-mediated pregnancy complications. Given the impact on women and perinatal heath, we will focus on current knowledge regarding the effects of ECS on nitrergic system in normal and pathological placentation.